Cerebral cavernous malformations (CCMs) are common, familial vascular malformations that cause strokes and seizures in midlife. Due to their location in the brain CCMs are virtually untreatable, making the development of novel therapies a priority. Positional cloning studies have identified mutations in three novel proteins, CCM1, CCM2 and CCM3, which interact biochemically but have no defined function. Convergent studies in zebrafish have shown that mutations in a novel cell surface receptor Heart of Glass (Heg), zCCM1, or zCCM2 give rise to a dilated heart during embryonic development. These studies identify a novel signaling pathway that regulates cardiovascular development and causes human vascular disease, but how this pathway functions is unknown. To begin to investigate this question, we have generated Heg-deficient and CCM2-deficient mice. We find that CCM2-/- and Heg-/-;CCM2 animals exhibit vascular defects and die prior to E10.5, while Heg-/- animals exhibit cardiac and vascular defects later in gestation and after birth. CCM2 knockdown blocks endothelial cord formation ex vivo and endothelial adherens junctions are abnormally shortened in the dilated chambers of fish lacking Heg or CCM2. We hypothesize that Heg receptors signal via CCM proteins in endothelial cells to regulate cardiovascular development and homeostasis by controlling cell-cell association. This proposal will test this hypothesis by addressing the following questions: i. What are the early developmental defects in CCM2-/- and Heg-/-;CCM2 mouse embryos? ii. What is the role of Heg-CCM signaling in endothelial, smooth muscle and cardiac muscle cells during cardiovascular development? iii. Do Heg receptors associate with CCM proteins at endothelial cell-cell junctions to regulate the formation and function of lumenized vascular structures? iv. Does CCM pathogenesis reflect an ongoing requirement for Heg-CCM signaling in the mature vasculature or are CCMs late manifestations of subtle developmental defects? The answers to these questions will provide new insight into vascular development and take the first steps toward the creation of new therapies for a human vascular disease.